Natural Killer (NK) cells play an important role in the control of viral infection before the establishment of a specific cytolytic T cell response mediated by CD3-positive MHC-restricted T cells. On the other hand, NK cells are involved in the rejection of bone marrow transplants. NK cells must receive a negative signal from target cells in order to spare them from lysis. The precise mechanism of target cell recognition by NK cells is still unknown. The aim of this study was (i) to determine which target cell elements control the recognition and lysis by NK cells, and (ii) to isolate molecular clones for the p58 NK receptor that is involved in transmitting the negative signal upon recognition of HLA class I molecules expressed by the target cells. It was demonstrated that the HLA-B27 allele of class I molecules can provide protection from lysis by a subset of NK clones. Furthermore, analysis of mutated HLA-B27 molecules revealed that different specificities existed even among HLA- B27-specific NK clones and that NK clones must distinguish between different conformations of HLA class I molecules. Purification of the p58 NK receptor was achieved and peptide sequences were derived that could be used to obtain molecular clones for p58 by recombinant DNA technology. The isolation of a complete cDNA encoding one of the members of the p58 receptor family revealed that this receptor represents a new protein belonging to the immunoglobulin superfamily.